Aberrant expression of OATP1B3 in colorectal cancer liver metastases and its clinical implication on gadoxetic acid-enhanced MRI

Park, Seung Hyun; Kim, Honsoul; Kim, Min Jung; Kim, Hogeun; Choi, Dong Kyu; Chung, Yong Eun; Kim, Do Young; Choi, Jin Young

doi:10.18632/oncotarget.20295

Cited by 17 publications

(11 citation statements)

References 25 publications

(30 reference statements)

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“…4). Although a large amount of hOATP1B3 protein was produced, confocal imaging indicated that the protein was distributed in the cytoplasm and not in the membrane, as is normally observed in hepatocytes (28). The cytoplasmic distribution of hOATP1B3 observed here is similar to the cytoplasmic distribution of aberrantly expressed hOATP1B3 observed in some tumors (24).…”

Section: Discussionsupporting

confidence: 71%

“…Confocal microscopy revealed that, unlike normal hepatocytes or CMV-hOATP1B3-transfected HEK293 cells, in which OATP1B3 is localized in the membrane (Fig. 1) (28), in CMV-Kozak-(codon-optimized) hOATP1B3-IRES-GFP-transfected cells, hOATP1B3 was localized mostly in the cytoplasm ( Supplementary Fig. 4).…”

Section: Transfection Of Hek293 Cells With An Overexpressing Hoatp1b3mentioning

confidence: 99%

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Human Organic Anion Transporting Polypeptide 1B3 Applied as an MRI-Based Reporter Gene

et al. 2020

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Objective: Recent innovations in biology are boosting gene and cell therapy, but monitoring the response to these treatments is difficult. The purpose of this study was to find an MRI-reporter gene that can be used to monitor gene or cell therapy and that can be delivered without a viral vector, as viral vector delivery methods can result in long-term complications. Materials and Methods: CMV promoter-human organic anion transporting polypeptide 1B3 (CMV-hOATP1B3) cDNA or CMV-blank DNA (control) was transfected into HEK293 cells using Lipofectamine. OATP1B3 expression was confirmed by western blotting and confocal microscopy. In vitro cell phantoms were made using transfected HEK293 cells cultured in various concentrations of gadoxetic acid for 24 hours, and images of the phantoms were made with a 9.4T micro-MRI. In vivo xenograft tumors were made by implanting HEK293 cells transfected with CMV-hOATP1B3 (n = 4) or CMV-blank (n = 4) in 8-week-old male nude mice, and MRI was performed before and after intravenous injection of gadoxetic acid (1.2 μL/g). Results: Western blot and confocal microscopy after immunofluorescence staining revealed that only CMV-hOATP1B3-transfected HEK293 cells produced abundant OATP1B3, which localized at the cell membrane. OATP1B3 expression levels remained high through the 25th subculture cycle, but decreased substantially by the 50th subculture cycle. MRI of cell phantoms showed that only the CMV-hOATP1B3-transfected cells produced a significant contrast enhancement effect. In vivo MRI of xenograft tumors revealed that only CMV-hOATP1B3-transfected HEK293 tumors demonstrated a T1 contrast effect, which lasted for at least 5 hours. Conclusion: The human endogenous OATP1B3 gene can be non-virally delivered into cells to induce transient OATP1B3 expression, leading to gadoxetic acid-mediated enhancement on MRI. These results indicate that hOATP1B3 can serve as an MRI-reporter gene while minimizing the risk of long-term complications.

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Section: Discussionsupporting

confidence: 71%

Section: Transfection Of Hek293 Cells With An Overexpressing Hoatp1b3mentioning

confidence: 99%

Human Organic Anion Transporting Polypeptide 1B3 Applied as an MRI-Based Reporter Gene

et al. 2020

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“…Future prospective, high-resolution, matched radiological-pathological correlation studies are required to determine whether this is also the case with gadoxetate. Prior studies with hepatobiliary-specific contrast agents have suggested that late gadolinium enhancement may be related to OATP1B3 expression and treatment response in a chemotherapy-naïve population [13,14].…”

Section: Discussionmentioning

confidence: 99%

Delayed tumour enhancement on gadoxetate-enhanced MRI is associated with overall survival in patients with colorectal liver metastases

et al. 2018

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Objectives To determine whether tumour enhancement on preoperative delayed-phase gadoxetate-enhanced MRI can predict long-term survival in patients with colorectal liver metastases (CRCLM) post-hepatectomy. Materials and methods Sixty-five patients who received a preoperative gadoxetate-enhanced MRI prior to liver resection for CRCLM from January 1, 2010, to December 31, 2012, were included in this retrospective study. Target tumour enhancement (TuEn) was calculated as the mean percentage increase in SNR from precontrast to 10-min or 20-min delayed phase for up to two target lesions. Per-patient TuEn was stratified into weak and strong enhancement based on the cut-off determined by the Youden Index for 3-year survival. Kaplan-Meier and Cox regression analyses were used to determine whether tumour enhancement could predict overall survival independent of potential confounders (clinical risk score). Results The proportion surviving at 3 years was 85.1% in patients with strong TuEn at 10 min vs. 56.5% in those with weak TuEn at 10 min (p = 0.001). The proportion surviving at 3 years was 79.4% in patients with strong TuEn at 20 min vs. 58.7% in those with weak TuEn at 20 min (p = 0.011). After adjusting for potential confounders, the hazard ratio of death was 0.24 (p = 0.009) in patients who had weak TuEn at 10 min and 0.32 (p = 0.018) in patients who had weak TuEn at 20 min. Conclusions Strong delayed tumour enhancement seen on gadoxetate-enhanced MRI is associated with overall survival in patients with CRCLM post-hepatectomy and may be useful for preoperative risk stratification. Key Points • Delayed tumour enhancement of colorectal liver metastases on gadoxetate-enhanced MRI is associated with survival post-hepatectomy • Delayed tumour enhancement of colorectal liver metastases on gadoxetate-enhanced MRI can be measured at both 10 min and 20 min post-contrast injection.

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“…The causative mechanism of this phenomenon is still debated; it has been suggested to be a slow accumulation of the contrast material within the intercellular matrix of the tumor [ 22 ] or an interstitial diffusion of the hepatobiliary contrast agent within areas of necrosis [ 67 ]. Another possible theory is the presence of aberrant expression of OATP1B3 in liver metastases as possible explanation of the hepatobiliary uptake; however, while Park et al [ 69 ] showed an increased expression of aberrant OATP1B3 (i.e., the protein involved in hepatocyte contrast uptake), Wlcek et al [ 70 ] showed that expression of OATP1B3 is downregulated while other OATPs are upregulated. The target appearance of metastases in the HBP (i.e., peripheral hypointense rim compared to central cloud of enhancement) resembles the peripheral washout pattern occurring in the delayed extracellular phases in 24% of metastases [ 71 ].…”

Section: Oncologic Patientsmentioning

confidence: 99%

Spectrum of liver lesions hyperintense on hepatobiliary phase: an approach by clinical setting

et al. 2021

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Hepatobiliary MRI contrast agents are increasingly being used for liver imaging. In clinical practice, most focal liver lesions do not uptake hepatobiliary contrast agents. Less commonly, hepatic lesions may show variable signal characteristics on hepatobiliary phase. This pictorial essay reviews a broad spectrum of benign and malignant focal hepatic observations that may show hyperintensity on hepatobiliary phase in various clinical settings. In non-cirrhotic patients, focal hepatic observations that show hyperintensity in the hepatobiliary phase are usually benign and typically include focal nodular hyperplasia. In patients with primary or secondary vascular disorders, focal nodular hyperplasia-like lesions arise as a local hyperplastic response to vascular alterations and tend to be iso- or hyperintense in the hepatobiliary phase. In oncologic patients, metastases and cholangiocarcinoma are hypointense lesions in the hepatobiliary phase; however, occasionally they may show a diffuse, central and inhomogeneous hepatobiliary paradoxical uptake with peripheral rim hypointensity. Post-chemotherapy focal nodular hyperplasia-like lesions may be tricky, and their typical hyperintense rim in the hepatobiliary phase is very helpful for the differential diagnosis with metastases. In cirrhotic patients, hepatocellular carcinoma may occasionally appear hyperintense on hepatobiliary phase.

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Aberrant expression of OATP1B3 in colorectal cancer liver metastases and its clinical implication on gadoxetic acid-enhanced MRI

Cited by 17 publications

References 25 publications

Human Organic Anion Transporting Polypeptide 1B3 Applied as an MRI-Based Reporter Gene

Human Organic Anion Transporting Polypeptide 1B3 Applied as an MRI-Based Reporter Gene

Delayed tumour enhancement on gadoxetate-enhanced MRI is associated with overall survival in patients with colorectal liver metastases

Spectrum of liver lesions hyperintense on hepatobiliary phase: an approach by clinical setting

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